Malignant Histiocytosis Research Articles

Difficult Diagnosis of Interdigitating Dendritic Cell Sarcoma of the Retroperitoneum: A Case Report and A Brief Review of the Literature.

Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm classified within the M-group of malignant histiocytoses. Its diagnosis poses a significant challenge. This article aims to describe a rare clinical case of IDCS and to illustrate the differential diagnostic process undertaken by the authors in establishing this diagnosis. A 60-year-old woman was admitted for the resection of a retroperitoneal mass discovered via CT scan. Morphological examination revealed a 7.5×5.5×5.0 cm tumor, encapsulated by a thin fibrous capsule. The tumor was composed of 90-95% inflammatory infiltrate with lymphocyte-like cells showing mature nuclear morphology (CD3+ and CD20+ cells) mixed with histiocytes and plasma cells, and 5-10% large polymorphic spindle-shaped cells expressing expression of CD45, CD68, CD1a, CD21, CD35, CD31, and CD34. An extensive immunohistochemical panel was performed to exclude various other tumors. Based on the morphology and immunophenotype, a diagnosis of IDCS was established. Further literature analysis indicated the nonspecificity of symptoms in patients with this tumor localization and variability in CD45 and CD68 staining in tumor cells, with consistent lack of expression of CD21, CD23, CD35, CD1a, and specific T- and B-cell antigens. IDCS is a rare and poorly understood tumor with a poor prognosis. The nonspecificity of clinical symptoms and the need for extensive morphological differential diagnosis render this entity a diagnosis of exclusion, requiring significant diligence from the pathologist.

Abstract 3835: Clinicopathologic determinants of survival in malignant histiocytic neoplasms: Analysis of a pooled database

Abstract Background: Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in these rare diseases. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 281 cases of MHN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 281 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 0-13 and 52-65. There was a male preponderance with M:F of 1.6. Primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), H&N (8%), and breast, heart, gonads, pancreas, and kidney (1% each). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median OS of the whole group was 12 months. BM involvement had a worse median OS (5 vs. 60 months, p=0.0002). Stage 1 disease had better median OS than higher stages (p=0.0008). Furthermore, unifocal had better median OS than multifocal/multicentric disease (60 vs. 7 months, p=0.0001). The presence of inflammatory background positively impacted OS (p=0.01). The occurrence of HPS adversely affected OS (p<0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 16 months, respectively (p=0.009). Among systemic therapies, SCT and BRAF/MEK inhibitors were superior to conventional chemotherapy (p=0.02). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size<10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age. Conclusion: This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS. Citation Format: Philip A. Haddad, Dinesh Keerty. Clinicopathologic determinants of survival in malignant histiocytic neoplasms: Analysis of a pooled database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3835.

Clinical characteristics, molecular aberrations, treatments, and outcomes of malignant histiocytosis.

Malignant histiocytosis (MH) is an extremely rare neoplasm of the macrophage-dendritic cell lineage. We report the clinical characteristics, molecular aberrations, treatments, and outcomes of patients with MH seen at two referral centers from January 2000 to May 2023. We identified 43 patients with MH, of which 26 had histiocytic sarcoma (MH-H), 9 interdigitating dendritic cell sarcoma (MH-IDC), and 8 Langerhans cell sarcoma (MH-LC). The median age at diagnosis was 61 years (range, 3-83). Thirty-three patients (77%) had multifocal disease, while 10 had unifocal involvement. Tumor specimens from 22 patients (51%) underwent targeted next generation sequencing, and 19 of 22 (86%) had at least one pathogenic mutation, including mutations in MAPK pathway genes (73%). The median overall survival (OS) among the entire cohort was 16 months (95% CI: 8-50). The outcomes of those with multifocal disease were significantly shorter than their unifocal counterpart: median OS of 10 months versus 50 months (p = .07). Patients with risk organ involvement (bone marrow, spleen, or liver) had significantly inferior outcomes. Chemotherapy and surgery were the most common first-line treatments for multifocal and unifocal disease, respectively. While the outcome for patients with multifocal disease was poor, there was a subset of patients who had durable responses to treatment. Our study highlights that MH has heterogeneous clinical presentation, frequent oncogenic mutations, and prognosis, which is strongly tied to disease extent and type of organ involvement.

Malignant Histiocytic Neoplasms' Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database

Background: Malignant histiocytosis, also known as the M-group per the Histiocyte Society classification, represents a rare, aggressive malignant group of histiocytic neoplasms. It includes histiocytic neoplasms that occur de novo (pMHN) and those that develop in association with other malignant diseases (aMHN). However, little is known about factors that impact MHN clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare histiocytic group. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 270 cases of MHN. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results: A total of 270 patients with confirmed MHN were identified, with 77% pMHN and 23% aMHN. The median age was 45, with bimodal peaks between 13-26 and 52-65. There was a male preponderance with M:F of 1.6. The most common primary sites of involvement were liver (15%), CNS and spleen (13% each), thoracic, GI, and soft tissues (12% each), bones (11%), skin (10%), and H&N (8%). Lymphadenopathy and bone marrow (BM) were involved in 28% and 18%, respectively. Constitutional symptoms occurred in 12% and hemophagocytic syndrome (HPS) in 6%. The median time of MHN onset in aMHN was 12 months. The median OS of the whole group was 12 months. BM involvement had a worse median OS (p = 0.003). Stage 1 disease had better median OS than higher stages (p = 0.01). Furthermore, unifocal had better median OS than multifocal/multicentric disease (p = 0.0005). The presence of inflammatory background positively impacted OS (p = 0.01). The occurrence of HPS adversely affected OS (p < 0.0001). Compared to no treatment, localized therapies such as surgery (S) and/or radiation therapy (RT) and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 3, 24, and 18 months, respectively (p = 0.02). When MHN was not amenable to complete resection, CT and CT+/-S+/-RT were superior to RT+S (p = 0.03). Having CNS or splenic-lymphatic primary involvement tended to have a numerical but non-significant worse median OS than soft tissue or visceral disease. While female sex, size<10cm, and pMHN seemed to have numerically better OS, they did not reach statistical significance. There was no difference in median OS for age. Conclusions: This study presents updated clinicopathologic data from a pooled cohort of patients with MHN. It identifies BM involvement, stage, extent of the disease, the inflammatory background status, occurrence of HPS, and treatment approach as critical determinants of OS.

Malignant Histiocytosis Comprises a Phenotypic Spectrum That Parallels the Lineage Differentiation of Monocytes, Macrophages, Dendritic Cells, and Langerhans Cells

Malignant histiocytoses (MHs), or the ‘M group’ of the Histiocyte Society classification, are characterized by neoplastic histiocytes with large pleomorphic nuclei. MH encompasses the diagnoses of histiocytic sarcoma, interdigitating dendritic cell sarcoma, and Langerhans cell sarcoma. We aimed to define the phenotypic spectrum of MH and examine the genotypic features across this spectrum. Using immunohistochemistry, we arranged the 22 cases into 4 subtypes that correspond to the lines of differentiation from monocytic and dendritic cell precursors as follows: (1) macrophage (n = 5): CD68+, CD163+, CD14+, and Factor 13a+; (2) monocyte-macrophage (n = 5): CD68+, CD163+, CD14+, S100+, and OCT2+; (3) dendritic cell (n = 6): CD68+, CD11c+, S100+, lysozyme+, ZBTB46+, and CD1a/langerin < 5%; and (4) Langerhans cell (n = 6): CD68+, CD11c+, S100+, ZBTB46+, CD1a+, and langerin+. The phenotypic subtypes align with those seen in low-grade histiocytic neoplasms as follows: MH-macrophage type correlates with Erdheim-Chester disease phenotype; MH-monocyte-macrophage type with Rosai-Dorfman disease phenotype, and MH-Langerhans cell type with Langerhans cell histiocytosis. Activating mutations in MAPK-pathway genes were identified in 80% of MH cases; 29% had mutations in the PI3k-AKT-mTOR pathway and 59% had mutations in epigenetic modulating genes. Strong expression of cyclin D1 was present in all cases, whereas p-ERK and p-AKT were not uniformly expressed. Eight of 22 (36%) MH cases were proven to be clonally related to a prior B-cell lymphoma. Defining the phenotypic spectrum of MH provides a guide to diagnosis and allows further exploration into the potential biological and clinical significance.

Treatment of Langerhans Cell Histiocytosis and Histiocytic Disorders: A Focus on MAPK Pathway Inhibitors.

Histiocytic disorders are rare diseases defined by the clonal accumulation of a macrophage or dendritic cell origin. These disorders include Langerhans cell histiocytosis, Erdheim-Chester disease, juvenile xanthogranuloma, malignant histiocytoses, and Rosai-Dorfman-Destombes disease. These histiocytic disorders are a diverse group of disorders with different presentations, management, and prognosis. This review focuses on these histiocytic disorders and the role of pathological ERK signaling due to somatic mutations in the mitogen--activated protein kinase (MAPK)pathway. Over the last decade, there has been growing awareness of the MAPK pathway being a key driver in many histiocytic disorders, which has led to successful treatment with targeted therapies, in particular, BRAF inhibitors and MEK inhibitors.

Molecular and clinicopathologic characterization of pediatric histiocytoses.

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.

High Prevalence of Epigenetic Mutations in Histiocytic and Dendritic Cell Disorders: Results from Molecular Analysis of a Large Cohort from Histiocytosis Working Group

Introduction Over the last decade, recurrent oncogenic alterations in the MAPK/ERK pathway have been discovered in various histiocytic and dendritic cell disorders, especially Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD). These discoveries have led to the successful use of targeted BRAF- and MEK-inhibitors. However, most data are derived from small institutional studies mostly focusing on ECD and LCH, which leaves room for a comprehensive evaluation of the molecular underpinnings in a large cohort. Methods Formalin-fixed paraffin embedded tumor biopsies from various histiocytic/dendritic cell disorders seen at a tertiary institution from 2001-2021 were subjected to whole exome sequencing (WES) using one of two assays: in-house SureSelectXT AllExon V5+UTR or commercially available Tempus xT assay. Identified variants were filtered to remove polymorphic, low coding impact and low read coverage variants. A variant was then selected for further analysis if it met one of the following criteria: 1) observed as somatic in ≥1 tumor-germline pairs or COSMIC database or 2) observed in at least three samples with an allele frequency of ≥10% in ≥1 sample. Cases were clustered into mutually exclusive groups based on their primary driver mutational profile using the following funneling order: BRAF-V600E (BRAF-V600E mutations), BRAF*/NRAS/KRAS (BRAF non-V600E, KRAS, or NRAS mutations), CSF1R (CSF1R mutations), MAPK (MAPK/MEK mutations), and PI3K (AKT3, INPP4B, MTOR, PIK3CA, PIK3R1, PIK3R2, PIK3R3, PPP2R1A, MTR mutations). A cancer specific pathway enrichment was performed on the unknown cases, which identified epigenetic mutations as major pathway alterations observed in the cohort. We also correlated the presence of epigenetic mutations with clinical features and outcomes. Results We included 114 cases with histiocytic and dendritic cell disorders in the study. Median age at diagnosis was 51y (IQR 37-64). The disease distribution was as follows: 46 LCH, 20 ECD, 17 RDD, 8 follicular dendritic cell sarcoma (FDCS), 1 adult xanthogranuloma, 12 malignant histiocytosis (MH; including histiocytic and Langerhans cell sarcoma), and 10 multicentric reticulohistiocytosis (MRH). Based on the known driver mutations in histiocytoses, the following 5 molecular groups were identified: BRAF-V600E (n= 19, 17%), BRAF*/KRAS/NRAS (n=17, 15%), MAPK (n=14, 12%), PI3K (n=8, 7%), CSF1R (n=2, 2%) (Figure 1). A large proportion (n=48, 42%) did not have any of the known driver mutations, while 6 cases (5%) had no alterations identified. Cancer-specific enrichment analysis in the entire cohort revealed mutations in epigenetic genes in 47 (41%) cases, including 30 (26%) cases with identifiable driver mutations and 17 (15%) cases without known driver mutations. Median number of epigenetic mutations was 1 (range 1-11); 21% cases had 2 and 10% cases had 3 epigenetic mutations, respectively. The most common epigenetic mutations included those in KMT2C (34%), KMT2D (23%), and ARID1A (19%). The mutational groups with highest prevalence of epigenetic mutations were CSF1R (100%), MAPK (71%), and PI3K (63%), while lowest prevalence of these alterations was found in BRAF-V600E group (16%; p=0.0003). The epigenetic gene mutations were seen more commonly in MRH (90%) and MH (50%) compared with ECD (45%), RDD (41%), FDCS (38%), and LCH (33%; p=0.037). There was no association between epigenetic gene mutations and age at diagnosis or organ involvement. The median overall survival (OS) was not significantly different between those with epigenetic mutations and those without such alterations (22y vs. 17y, p=0.89). Conclusions In this large study of patients with diverse histiocytic and dendritic cell disorders, we found a high prevalence of mutations in epigenetic genes (41%). These mutations were specifically enriched in tumors with non-BRAF-V600E mutations, and in MRH/MH. These data shed light on additional mechanisms of disease pathogenesis, and with available epigenetic therapies, warrant further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Langerhans cell histiocytosis in adults: literature review

Langerhans cells histiocytosis is a variant of malignant histiocytosis. The course and symptoms vary. patients with localized forms have a better prognosis, because local therapy is effective. patients with multifocal forms of histiocytosis receive systemic drug therapy, which cures some of the patients. This review provides up-to-date data about typical presentation of the organ involvement, diagnosis, course and therapy of various forms of Langerhans cells histiocytosis.

Tumor Mutational Burden in Histiocytic Neoplasms

▪BackgroundHistiocytic disorders are rare hematologic neoplasms characterized by their high clinical heterogeneity. Evidence of constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in a number of these disorders has led to the increasing use of BRAF- and MEK-inhibitors as a therapeutic strategy. Response to these therapies is not universal and additional effective treatment options are required. Immune checkpoint inhibitors have proven effective for a wide array of malignancies. Tumor mutational burden (TMB), the total number of somatic pathogenic variants per coding region in a tumor genome, is a clinical biomarker associated with response to immunotherapy. We have previously reported preliminary findings of low TMB in a small cohort of patients with histiocytic neoplasms (Goyal G et al. Blood 2019). In this study, our aim was to confirm the findings in a larger clinical cohort using next generation sequencing studies.MethodsA retrospective review of adult patients consecutively seen at Mayo Clinic from 2017 to April 2021 and diagnosis of a histiocytic neoplasm was performed. Electronic records were queried for demographic and laboratory data of all patients who consented to undergo tumor-tissue next-generation sequencing with the Tempus-xT ® or xO ® assay (Chicago, IL), throughout the course of their evaluation. TMB was reported as the number of nonsynonymous mutations per coding area of a tumor genome. TMB across groups was compared via an independent-samples T-test or via analysis of variance and post hoc subgroup testing via Turkey's Test as required.ResultsSeventy-three patients were included in the study. Individual diagnoses included: Erdheim-Chester disease (ECD) in 31.5% (n=23), including 3 patients with overlap features of ECD and other histiocytoses; Rosai Dorfman disease (RDD) in 28.8% (n=21); Langerhans cell histiocytosis in 21.9% (n=16), histiocytic sarcoma (HS) in 5.5% (n=4), and other histiocytic neoplasms in 12.3% (n=10) including adult xanthogranuloma, xanthoma disseminatum, undifferentiated histiocytoses, and one case of Langerhans cell sarcoma.Median tumor percentage on analyzed samples was 30% (range 10%-90%) and was ≤20% in 29 samples. TMB was <1.0 mutations per megabase (mpMb) in 42.5% (n=31) and >5.0 mpMb in only 6 cases. Median TMB was 1.58 (range 0 - 5.26) for ECD, 1.08 (range 0 - 6.3) for LCH, 0.2 (range 0 - 5.8) for RDD, 3.19 (range 1.67 - 6.8) for HS, and 1.6 (range 0 - 7.5) for other histiocytic neoplasms (Figure 1). No clear association between increasing TMB and number of systems with histiocytic infiltration was observed (Figure 2). A significant increase in TMB was observed among the 5 cases of sarcoma as compared to the rest of the cohort (p=0.014). When not considering sarcomas, no differences were observed in TMB between patients with ECD, LCH, RDD or other histiocytoses (F=0.775; p=0.512).ConclusionIn this large cohort of histiocytic disorders, TMB was low compared to that historically seen in other neoplasms though this is likely influenced by tumor purity ≤20% in 29 cases. Only 6 tumors had TMB reports with mpMb above the threshold thought to be associated with an increased likelihood of response to PD-1/PDL1-targeted therapies (>5 mpMb). Our results suggest a low likelihood of response among histiocytic disorders using immune checkpoint inhibitors. Further exploration among malignant histiocytoses (HS and Langerhans cell sarcoma) is warranted given our findings of higher TMB compared with other histiocytic neoplasms. [Display omitted] DisclosuresBennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board.

Recommendations for Managing Adults With Histiocytic Neoplasms: New NCCN Guidelines

The histiocytoses, a group of clonal and reactive conditions, arise from monocytic macrophage or dendritic cell lineages. The current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Histiocytic Neoplasms reflect the most up-to-date, evidence-based data relating to the evaluation and management of this disease. Specifically, the guidelines focus on adult Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease. Because these disorders are rare, challenges have arisen regarding clinical suspicion, histologic diagnosis, treatment, and molecular subtyping. Future versions of the NCCN Guidelines will address the diagnosis and management of pediatric patients, as well as malignant histiocytosis.

Histiocytic disorders.

The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207+ antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.

P-045: Immunoglobulin V(D) J Recombination, Protein Ubiquitination, Cell Adhesion and Sonic Hedgehog Gene Variants are detected among familial Multiple Myeloma subjects following whole exome sequencing

<h3>Background</h3> Familial multiple myeloma(MM) cases have been associated with some rare, germline variants, mostly among epigenetic modification genes and needs to be validated in other populations. The aim of this study is to investigate formerly reported rare variants in our population and to search for additional ones. <h3>Methods</h3> Following the ethical committee approval, hematology centers in Turkey were informed for collaboration in this familial MM genetic association study. Inclusion criteria was defined as having one or more first, second or third degree relatives who have plasma cell diseases. After obtaining informed consents, patients' peripheral blood samples or DNAs from pathological samples were collected. NGS analysis have been performed on 33 samples from 23 families, targeting 14 variants in 6 genes, previously reported to be associated with familial presentation (EP300, CDKN2A, USP45, ARID1A, KDM1A, DIS314)(Pertesi et al., Leukemia, 2020). To widen the range of analysis, whole exome sequencing (WES) within 3 families (6 patients) of first degree relatives were carried out. The detected variants were checked against NCBI's dbSNP. Mutation Taster was utilized for probable disease associations. <h3>Results</h3> 30 MM families(63 patients) were included. Of the patients 69% were first, 4% were second and 27% were third degree relatives. Neither of the previously reported rare variants were detected among the subjects in the targeted sequencing. However, an heterozygote variant (rs3731249) close to the targeted region in CDKN2A was detected in 3 patients. WES detected new variants which were not observed earlier. Family 1:Missense variants in BRIP1 (function: DNA double strand break repair)(rs886053214, rs886053215) and ACD (function: maintain telomere length)(rs1306270247). All of which were predicted as polymorphism, in silico. Family 2:Missense variant in RAG2 (function:V(D)J recombination of Ig and T cell receptor) (rs765298019) predicted as disease causing. Family 3:Missense variant in RET (function: receptor tyrosine kinase)(rs1366681125) predicted as polymorphism. Missense variants in CBL (function: protein ubiquitination)(rs754194646), APC (function: cell adhesion)(rs760591046) and PTCH1 (function: sonic hedgehog) (rs772574714) were predicted as disease causing. All of the variants from the patients were detected as one-copy-alleles. The variant in RAG2 was reported to cause severe combined immunodeficiency and histiocytic medullary reticulosis in homozygous state. The PTCH1 variant is known to give rise to nevoid basal cell carcinoma syndrome. Germline mutations of CBL and APC are related to the juvenile myelomonocytic leukemia, familial AML and familial adenomatous polyposis respectively. <h3>Conclusion</h3> MM development is a multistep process. As of actual literature, MM susceptibility in familial cases involve various gene variants. Here we suggest the consideration of RAG2, CBL, APC, PTCH1 as additional loci for the progression to familial MM.

Incidence, Treatment Patterns, and Outcomes of Histiocytic Disorders in the United States: A Forty-Year Population Study

BackgroundLangerhans cell histiocytosis (LCH) is an orphan disease of clonal dendritic cells, which can affect any organ of the body. There is paucity of data on treatment patterns and outcomes of adult LCH pts, who are usually treated with pediatric-based therapies. No prospective clinical trial has been conducted to date to identify optimal therapeutic strategies in adult LCH. Uncertainty of the natural history of LCH in adults including its pathogenesis, treatment patterns, and outcomes have limited development of novel treatments. Here, we used the Surveillance Epidemiology and End Results (SEER) to describe the epidemiology of LCH, trends in treatment practices over time, and survival outcomes over a forty-year period.MethodsAll 18 registries of SEER covering a period from 1973 to 2014 was used to assemble LCH cohort. LCH cases included in the study had a diagnosis of malignant histiocytosis or LCH (unifocal, multifocal, disseminated, or not otherwise specified). Descriptive data on incidence, demographics, and treatment were collected. Relative survival (RS) was stratified by 5-year (yr) time increments, four age groups [< 20 years (yrs) - pediatric; 20-39 yrs; 40-59 yrs, and > 60 yrs - elderly], and treatment type was estimated using the Kaplan-Meier method and compared between groups using the log-rank test. As LCH pts tend to live longer, we calculated RS probabilities, which compares survival in the pt cohort with the expected survival of the general population having the same characteristics with respect to age, sex, race, and calendar period. Survival probabilities were calculated using the SEER Survival System (SEER*Stat). RS estimates (proportion of cancer pts surviving for a specified period) were calculated by the life table method. Analysis was performed using SEER*Stat.ResultsA total of 1480 LCH pts were identified who met the inclusion criteria. Of these, 55% were male, 82% Caucasians, and 58% of cases were diagnosed in the pediatric age group (age <18). The incidence rate remained stable from 1973 to 2009 with an average of 17 new cases per year at an age-adjusted incidence rate of 0.3 per 1,000,000. However, introduction in 2010 of a new International Classification of Diseases code resulted in a significant increase in recorded cases from that year going forth. A variety of treatment modalities were used including 47.8% receiving chemotherapy, 26.2% receiving surgery, and 10.3% receiving radiation therapy. Survival analysis of available SEER data on 705 LCH pts showed a median RS of 16.2 years with 52% of pts alive at 25 yrs. Survival rates have steadily improved since 1973 when assessed in 5-yr increments and since 2003, survival rates have remained steady at 90% (Figure 1). When analyzed by age groups, survival rates successively worsened with advancing age groups with 80% of pediatric pts alive two decades from diagnosis compared to no survivors in the elderly group (Figure 2). In treated pts, receipt of chemotherapy or radiation therapy at diagnosis conferred no survival benefit over those not receiving such treatments (Figures 3 and 4). Likewise, pts receiving surgery at diagnosis did not have significant survival benefit over those not treated with surgery (Figure 5). Notably, 34.1% of the 1480 pts died due to a hematologic malignancy, while 13.1% died due to a solid tumor malignancy. In those who later developed second cancers, there was a significant risk of solid tumor (Odds ratio (OR) 1.69, 95% CI 1.08-2.51, P < 0.05) and hematologic malignancies (OR 4.89, 95% CI 1.96-10.07, P < 0.05).ConclusionTo our knowledge, this is the first population based study to examine treatment and survival trends in histiocytic disorders, which remain rare and poorly characterized. Notable observations from this study show no relative survival benefit with chemotherapy, radiation therapy, or surgery indicating these treatments were mainly to control local or systemic disease. As such, novel therapeutic approaches are needed to improve outcomes. Although this study shows consistent survival gains since 1973, this is likely due to improvements in supportive care practices. Unfortunately, outcomes in the elderly are dismal compared to pediatric pts. While pts with histiocytic disorders generally have a long duration of remission, we demonstrate that they are at risk for second cancers, particularly hematologic malignancies. [Display omitted] DisclosuresGerds:Incyte: Consultancy; CTI BioPharma: Consultancy. Advani:Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees.

Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma.

BackgroundHistiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim‐Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking.MethodsTumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer‐related genes.ResultsAmong the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen‐activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF‐κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance.ConclusionA total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors.Implications for PracticeThis study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF‐κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.

Histiocytosis and Neoplasms of Macrophage-Dendritic Cell Lineages: Multimodality Imaging with Emphasis on PET/CT.

Histiocytosis is a rare inflammatory process characterized by pathologic infiltration and accumulation of cells derived from the monocytic lineage in normal tissue. It encompasses more than 100 different subtypes of disorders that were recently classified into five main groups: (a) Langerhans-related histiocytosis, (b) Rosai-Dorfman histiocytosis, (c) cutaneous and mucocutaneous histiocytosis, (d) malignant histiocytosis, and (e) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Langerhans cell histiocytosis is the most common histiocytic disorder. Less common types include Erdheim-Chester disease, Rosai-Dorfman disease, adult and juvenile xanthogranuloma, necrobiotic xanthogranuloma, histiocytic sarcoma, interdigitating dendritic cell sarcoma, Langerhans cell sarcoma, and hemophagocytic lymphohistiocytosis. Although the pathogenesis of these disorders may be attributable to mutations in the oncogenic driver, recent discoveries have shown that inflammation and fibrosis secondary to mutated histiocytes, rather than a proliferative cell mechanism, result in manifestation of the disease. Diagnosis, which relies on a multidisciplinary approach, is challenging and often delayed because clinical findings are nonspecific and may mimic malignant processes at radiologic evaluation. Compared with conventional imaging, PET/CT allows detection of the increased metabolic activity in histiocytes. Diagnostic algorithms for histiocytic disorders should include functional imaging with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT, which provides a comprehensive whole-body evaluation of their potential involvement with multiple organ systems and allows monitoring of therapeutic response. The most recent revised classification, pathophysiologic and clinical manifestations, sites of involvement, and imaging features of histiocytosis are described in this review and a multimodality approach is used, with emphasis on 18F-FDG PET/CT evaluation. ©RSNA, 2021.

Abstract A37: Unique gene fusions inform targeted therapeutic strategies across extremely rare, non-CNS pediatric solid tumors

Abstract Introduction: In children, approximately 7% of the non-CNS solid tumors include extremely rare histologies such as angiosarcomas and histiocytic neoplasms. While most recurrent histologies can be identified with a commonly occurring alteration or associated with a known biologic mechanism, rare solid tumors remain poorly characterized given their low frequency of occurrence and intrapatient tumor heterogeneity. Our group and others have demonstrated gene fusions (GFs) as unique oncogenic alterations in pediatric gliomas to guide prognosis, diagnosis, and therapeutic interventions. Here, we investigated the role of unique GFs as individualized therapeutic targets in 3 patients with rare non-CNS malignancies and explored GF-directed precision medicine approaches. Methods: We selected a patient with the rare diagnosis of pediatric angiosarcoma (pAS) and two with pediatric histiocytic neoplasms spanning the juvenille xanthogranuloma (JXG) family and malignant histiocytoses groups. Neoplasms were analyzed using the CHOP Comprehensive Next-Generation Sequencing Solid Tumor Panel as well as a targeted RNA-seq panel for 106 fusion partner genes. For novel gene fusions identified, we performed molecular and therapeutic characterization, including subcloning to create heterologous cell models. Cellular assays were used to assess oncogenic transformation, test mechanistic activation of related downstream signaling pathways via cellular assays, and examine targeting of GFs with specific small-molecule inhibitors. Results and Discussion: We identified a novel NOTCH1-ROS1 gene fusion in pAs, and rare BRAF-fusions, MTAP-BRAF and MS4A6A-BRAF, in malignant and JXG family histiocytic neoplasms, respectively. We also identified a germline TP53 p.T123Wfs*12 pathogenic variant, and the cancer predisposition team confirmed Li Fraumeni syndrome in the angiosarcoma patient. Our studies demonstrate that the NOTCH1-ROS1 fusion and both BRAF-fusions are potent oncogenes capable of inducing neoplastic transformation in cells and tumor formation in a murine allograft model. The kinase domains of ROS1 and BRAF are retained and activate the MAPK/PI3K/mTOR and JAK-STAT pathways in respective GF- expressing models, driven by potent dimerization of the GFs. Upon testing ROS1-targeted tyrosine kinase inhibitors (TKI) against NOTCH1-ROS1, we observe dose-dependent suppression of Notch1-Ros1 driven cellular activity and concurrent inhibition of tumor growth as well as prolonged survival after oral monotherapy. Interestingly, BRAF-fusions do not respond to second-generation BRAF inhibitors but can be suppressed by RAF dimer-inhibitor LY3009120 and MEK inhibitors. Overall, these data suggest that ongoing genomic profiling of rare pediatric tumors may reveal actionable drivers, and molecular testing of putative oncogenic fusions is imperative for improvement of patient outcomes through precision therapy. Citation Format: Payal Jain, Lea F. Surrey, Joshua Straka, Tiffany Smith, Sudarshan Iyer, Elizabeth Fox, Monika Davare, Jennifer Picarsic, Marilyn Li, Angela J. Waanders, Adam C. Resnick. Unique gene fusions inform targeted therapeutic strategies across extremely rare, non-CNS pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A37.

Canine tonsillar neoplasia and tonsillar metastasis from various primary neoplasms.

Tonsillar metastasis from distant primary tumours has not been described in dogs, and reports are rare in humans. The aims of this study were to determine whether tumour metastasis occurs to the canine palatine tonsils and evaluate whether afferent lymphatics drain to the palatine tonsils via skull indirect computed tomography lymphangiography (ICTL). Retrospective review of the diagnostic laboratory tonsillar histopathology submissions was performed. ICTL studies (n = 53) were retrospectively reviewed by a single radiologist. Of 882 total tonsil histopathology samples, 492 (56%) were considered neoplastic, with 8% of them benign. Of the primary malignant neoplasms of the tonsil, squamous cell carcinoma (55%), lymphoma (17%) and melanoma (12%) were most common. Tonsillar metastasis was confirmed in 41 cases; histopathologic evaluation revealed melanoma (25), carcinoma (10), hemangiosarcoma (2) and one each of fibrosarcoma, malignant histiocytosis, basal cell tumour and undifferentiated sarcoma. A total of 53 tonsillar melanoma cases were identified, of which 25 represented metastasis from a known distant primary tumour and 28 were solely tonsillar, with 9 of these cases having concurrent lymph node metastasis. No ICTL cases had lymphatic contrast drainage to the palatine tonsil. The palatine tonsil is an important site of metastasis for a variety of primary tumour types from many locations. ICTL did not reveal lymphatics draining to the palatine tonsil, which is highly supportive of hematogenous route of metastasis to the tonsil. Tonsillar metastasis may be more common than previously thought. It is recommended to perform a thorough oral examination, including the tonsils, for all oral tumours and melanoma cases.

Histiocytosis in the dermatological context of the new classification

Histiocytoses comprises aheterogeneous group of inflammatory diseases for which dendritic cells and macrophages are the main cellular components. The inflammatory infiltrate can affect the skin and other organs, and clinical outcome varies from mild to lethal depending on the involved cell subset and organ infiltration as well as comorbidities. Until recently, the group of histiocytosis was divided into Langerhans cell histiocytosis, non-Langerhans cell histiocytosis and malignant histiocytosis. With the new classification from JF Emile etal., the subgroups were determined regarding clinical, histiopathological, radiological, phenotype, genetic, and molecular features. In this review, we explain the revised classification with emphasis on dermatological and molecular aspects.

Albumin fusion improves the pharmacokinetics and in vivo antitumor efficacy of canine interferon gamma

Interferon (IFN)-γ plays an important role in antiviral, anti-proliferative, immunomodulatory and pro-inflammatory activities. However, the short therapeutic half-life of IFN-γ lessens its efficacy. Albumin fusion strategy is one of the most effective ways to improve the pharmacokinetic properties of cytokines. In this study, N- and C-terminal canine albumin fusions with canine IFN-γ were expressed in the baculovirus expression system. The fusion proteins stimulated Stat1 phosphorylation at levels similar to that of the recombinant IFN. The antiviral, anti-proliferative and promote apoptosis activity of CSA-IFN-γ was lower than IFN-γ-CSA and both were less than that of recombinant IFN-γ. In vivo pharmacokinetics demonstrated a significantly longer half-life for CSA-IFN-γ (21.73 h) than for IFN-γ-CSA (6.51 h) and canine reIFN-γ (2.22 h) in Wistar rats. CSA-IFN-γ was also more effective than IFN-γ-CSA and canine reIFN-γ at inhibiting growth of canine renal malignant histiocytosis in nude mice. Our results indicated that a canine serum albumin fusion at the N-terminus of IFN-γ prolongs its half-life and improves its in vivo antitumor activity.